Muscle matters: Skeletal muscle index and body mass index impact on complications and survival in renal cancer

Abstract Objective The objective of this study is to independently assess skeletal muscle index (SMI) and body mass index (BMI) as prognostic determinants for renal cell carcinoma (RCC) and investigate their correlation with surgical outcomes. Patients and methods A retrospective cohort study of 524 RCC patients diagnosed between August 2010 and July 2018 was conducted using data from the Zealand University Hospital Renal Cancer Database in Denmark. Patient information was extracted from electronic patient records and the National Cancer Registry and encompassed demographics, clinical factors, tumour characteristics and surgical details. SMI was calculated from a single third lumbar vertebra (L3) axial computed tomography (CT) image via CoreSlicer software and classified into high using gender‐specific thresholds. Primary outcomes focused on complications within 90 days as well as survival outcomes, and their relation with both SMI and BMI. Multivariable analysis assessed SMI's independent prognostic significance in RCC. Results Among 524 patients, 18.5% experienced complications, with high SMI correlating significantly (p = 0.018) with a 72% higher complication risk. High SMI patients had a 22.7% complication rate compared to 14.5% in the low SMI group. High SMI was also linked to prolonged survival (110.95 vs. 94.87 months; p = 0.001), whereas BMI showed no significant survival differences (p = 0.326). Multivariable analysis (n = 522) revealed high SMI associated with improved survival (hazard ratio [HR] = 0.738; 95% CI, 0.548–0.994; p = 0.046). Advanced T‐stage significantly impacted mortality (T2: HR = 2.057; T3: HR = 4.361; p < 0.001), and each additional year of age raised mortality risk by 4.3% (HR = 1.043; p < 0.001). Conclusions Higher SMI increases the risk of postoperative complications, yet it significantly improves overall survival rates. Different BMI categories lack RCC prognostic significance. The increasing incidence in RCC calls for the use of CT scan to assess SMI and aid treatment planning in patients who might benefit from preoperative interventions.

Conclusions: Higher SMI increases the risk of postoperative complications, yet it significantly improves overall survival rates.Different BMI categories lack RCC prognostic significance.The increasing incidence in RCC calls for the use of CT scan to assess SMI and aid treatment planning in patients who might benefit from preoperative interventions.

K E Y W O R D S
body mass index (BMI), overall survival, postoperative complications, renal cell carcinoma, skeletal muscle index (SMI)

| INTRODUCTION
The incidence of renal cancer has been rising steadily since the 2000s and accounted for 430 000 total cases in 2020, ranking as the 14th most common cancer worldwide. 1Numerous prognostic factors have already been identified, such as smoking status, hypertension, and male gender. 2Body mass index (BMI) is associated with increasing risk of developing renal cell carcinoma (RCC). 1 Interestingly, data establish a correlation between higher BMI and improved cancer-specific survival (CSS), alongside augmented recurrence-free survival (RFS) [3][4][5] and prolonged overall survival (OS) in overweight and obese patients compared to those of normal weight. 6Kott et al. revealed diminished postoperative complications subsequent to nephrectomy in patients with a BMI up to 30 kg/m 2 , 7 reinforcing the 'obesity paradox' and emphasizing that BMI alone is an insufficient prognostic indicator for RCC outcomes.
Shifting focus, the skeletal muscle index (SMI), frequently evaluated through the third lumbar vertebra (L3) index, has emerged as a promising replacement instead of BMI, accurately reflecting body composition as assessed by computed tomography (CT scan) of the L3.The threshold value for SMI was chosen based on its association with decreased survival, which is linked to weight loss exceeding 8%.This selected threshold predicts nearly half of the population's risk. 4][10] Notably, a confluence of evidence suggests that patients exhibiting both sarcopenia and higher BMI tend to experience higher rates of surgical complications. 11Beyond the confines of RCC, SMI has demonstrated efficacy in prognosticating post-surgical outcomes in colorectal and lung cancer, irrespective of BMI variations. 12,13is highlights a potentially complex interplay between these measures, urging further research of the distinct roles of BMI and SMI as autonomous prognostic determinants for RCC.Thus, the present study seeks to compare BMI and SMI as independent prognostic factors for RCC and the association between both measures and surgical outcomes.

| Study population and data source
We conducted a retrospective cohort study, identifying 524 patients diagnosed with localized RCC from August 2010 to July 2018, using the Zealand University Hospital Renal Cancer Database.The study involved meticulous data extraction of variables including Eastern Cooperative Oncology Group (ECOG) performance status, surgical approaches, age, gender, BMI, Charlson score, pathological findings and smoking status.In cases of missing data, medical personnel involved in the patients' care reviewed patient electronic journals.

| Body composition analysis
Body composition parameters were ascertained using a single axial CT image at the L3.Images were analysed using the free open-source web-based software package CoreSlicer (version 1.0.0;Montreal, Quebec, Canada), 14 applying predefined density thresholds in Hounsfield units (HUs): 29 to +150 for skeletal muscle (SM), À190 to À30 for subcutaneous adipose tissue (SAT) and À150 to À50 for visceral adipose tissue (VAT).Total cross-sectional areas of SM, VAT and SAT were measured in cm 2 , and average HU densities were documented for skeletal muscle density (SMD).Manual segmentation correction for the selected area was performed.Subsequently, cross-sectional areas were height-normalized (m 2 ) to derive the SMI (cm 2 /m 2 ).L3SMI was labelled high if it is more than 53 cm 2 /m 2 for males and more than 41 cm 2 /m 2 for females. 15

| Clinical data collection
Tumour attributes including clinical and post-surgical TNM stage, Fuhrman grade and morphology, in addition to treatment details such as the type and date of surgery, were obtained from the NCR.
Preoperative details (body weight, height, smoking status, American Society of Anaesthesiologists [ASA] score), and perioperative data, encompassing complications, Clavien Grade classification, length of hospital stay (LOS), surgical blood loss refers to the bleeding that occurs during an operation and may necessitate a blood transfusion, and surgical time, were meticulously extracted from medical records by data managers from IKNL.

| Outcome measures
The primary outcomes assessed were the impacts of SMI and BMI on oncological outcomes and complications.2).

| Multivariable analysis
Five hundred twenty two patients (99.6%) were included in the final multivariable analysis (Table 3).The model assessed the impact of

| DISCUSSION
In our investigation, a substantial correlation emerged between SMI and complications, wherein a higher SMI was associated with an increased incidence of complications.Conversely, BMI exhibited no significant influence on either survival time or the rate of complications.Our multifactorial analysis identified SMI, T-stage and age as notable prognostic factors affecting survival and mortality.

| Survival analysis
Our study discerned a noteworthy disparity in mean survival time between patients with high and low SMIs.Our results revealed no significant variance across the three BMI groups.Notably, the obese BMI group exhibited the highest estimated mean survival time,  T A B L E 3 Multiple variable analysis with cox regression.High skeletal muscle index (SMI) was associated with better survival.The higher T-stage, the higher risk of mortality.higher SMI, and both groups demonstrate improved mortality risk assessment.
Additionally, our investigation revealed that lower SMI, advanced T-stages and an annual increase in age were associated with reduced survival times in our multifactorial analysis.The consistent recognition of sarcopenia at diagnosis as a risk factor for diminished OS in prior studies 9,10,19 supports the validity of our findings.Regarding T-stage, a majority of our cohort presented with advanced T3 stage tumours, consistent with another study demonstrating significantly higher tumour stages in sarcopenic patients, albeit in univariable analysis. 20ch patients might face an increased risk of recurrence, as supported by Noguchi et al., 21 who established a higher T-stage as an independent predictor for poor RFS in a multivariable study.Nevertheless, further investigation within our patient cohort would be pivotal to conclusively affirm this data.Lastly, our analysis revealed that older patients experienced diminished survival times, with a 4.3% increase in the likelihood of death per year.This observation aligns with similar findings by Liu et al. 20 and other researchers, where age was identified as an independent predictor of sarcopenia, 22 subsequently linked to poorer OS.

| Complications
The univariate statistical analysis demonstrated that neither the type of surgery nor gender exerted a discernible influence on the incidence of complications.However, a distinct correlation surfaced between SMI and complications.High SMI individuals displayed a notably heightened propensity for complications compared to their low SMI counterparts.This contradicts Schmeusser et al.'s prior research, which posited that sarcopenia, or low SMI, lacks predictive capacity for major postoperative complications within 90 days for individuals with non-metastatic renal cell carcinoma (nmRCC. 23netheless, low SMI did exhibit a correlation with reduced OS.Despite a varied distribution of complications across BMI categories highlighted in cross-tabulation, subsequent statistical analyses failed to establish a significant correlation between BMI category and the occurrence of complications.This challenges the assertion by Maurits et al. that obesity correlates with major postoperative complications following nephrectomy. 24Furthermore, a previous metaanalysis encompassing surgical outcomes post laparoscopic and partial nephrectomy in both obese and non-obese patients revealed a higher prevalence of Clavien grade 3 or higher complications in the obese cohort. 25Notably, this study did not integrate observations on sarcopenia.
Regarding gender, several studies have established a link between male gender and an elevated probability of developing sarcopenia. 9,10 An examination of obese patients found that male gender independently predicted increased blood loss and longer operative durations. 26Intriguingly, a substantial portion of our male patients exhibited low SMI.However, it is important to note that gender did not emerge as a significant factor in either univariate or multivariate analyses in the current study.

| Prehabilitation
Smaller studies have been done on the effect of preoperative exercise therapy on postoperative outcomes.Gillis et al. 27 found that in patients undergoing tumour resection for colorectal cancer, a preoperative intervention had a significant positive effect on recovering to or above baseline compared to a postoperative intervention.Similarly, Valkenet et al. 28 found that preoperative exercise intervention could reduce time of hospital stay and reduced rate of complications.Our findings may assist in further research on these topics combined in the hopes of further improving patient outcomes in both the shortand long-term postoperative period.

| Limitations of the study
This study used high-quality cancer data to produce a better understanding of the impact both SMI and BMI have on RCC prognosis.
Despite that, it is limited by the retrospective design of and by the number of the patients included, because it was conducted in a single centre.This increases the risk of selection bias within our study, and therefore, no comment can be made on whether the results are applicable for all postoperative RCC patients.However, the comparisons of country specific results are relatively reliable.

| Conclusion
The association between higher SMI and increased postoperative complication risks, despite its significant improvement in OS rates, underscores the need to distinguish high-risk RCC patients for precise treatment planning.However, different BMI classifications show no statistical significance in RCC prognostication, emphasizing the pivotal role of SMI assessment through CT scans.
Amidst the rising incidence of RCC, utilizing CT scans to evaluate SMI and related components emerges as a critical strategy in identifying patients poised to benefit from tailored preoperative interventions.This comprehensive approach aims not only to enhance survival but also to mitigate complications, marking a crucial advancement in RCC care planning.
In clinical decision-making, acknowledging SMI's importance holds immense value, prompting the consideration of personalized care strategies.These findings underline the potential benefits of integrating SMI assessment into treatment paradigms, thereby bolstering survival rates and refining the care trajectory for individuals with RCC.
Hillers.Data curation and writing-review and editing: Signe Wang Bach.
Conceptualization, writing-review and editing, data curation and methodology: Atena Saito.
Of 524 patients stratified by the SMI, 268 had a low SMI, while 256 were classified as high SMI.The overall mortality rate in the follow-up period was 37.4% (n = 197): 119 deaths occurred in the low SMI group and 78 in the high SMI group.The average age was 64.2 years (SD, 10.7 years).Patients were further categorized by BMI: 185 normal weight, 198 overweight and 141 obese.Mortality rates were 42.7% (n = 79) for normal weight, 35.4% (n = 70) for overweight and 34.0%(n = 48) for obese.Complications were seen in 17.8% (n = 33) of the normal weight, 15.2% (n = 30) of the overweight and 24.1% (n = 34) of the obese group.The correlation coefficient suggests a moderate positive relationship between BMI and SMI (r = 0.395, p < 0.001; 95% CI, 0.321 to 0.465) (Table 1 corroborated these findings, highlighting a BMI of 23 kg/m 2 or higher as conducive to better OS, which are consistent with our univariate and multivariate analyses among RCC patients.Furthermore, Hasselager and Gögenur 18 in a systematic review found that sarcopenia correlated with heightened mortality rates, both short and long term, in patients undergoing major abdominal surgery.Consequently, considering higher BMI as a protective factor against mortality in RCC aligns with our results, indicating a significant positive correlation between SMI and BMI via the Pearson correlation coefficient.This correlation suggests that a higher BMI tends to be associated with a F I G U R E 1 Survival time of skeletal muscle index (SMI) groups with high SMI having a bigger fraction with longer survival time.F I G U R E 2 Survival time of body mass index (BMI) groups with normal BMI.
). Basic characteristics of study population and tumour characteristics sorted in two groups according to skeletal muscle index (SMI).
group, and 58/524 (11.1%) were in the high SMI group.There was a significant association between SMI and complications ( p = 0.018); high SMI conferred 72% increased odds of complications (95% CI, 1.099-2.693).The absolute risk for complications was 22.7% in the high SMI group compared with 14.5% in the low SMI group.However, no significant association was found between complications and BMI ( p = 0.107) (Table1).3.3 | Survival analysis